In U.S. Pat. No. 3,320,124, issued in 1967, there is described and claimed a method for treating coccdidiosis with quinazolinone derivatives.
Halogufinone, otherwise known as 7-bromo-6-chloro-3-3-(3-hydroxy-2-piperidinyl)-2-oxopropyl!-4(3H)-quinazo linone, was first described and claimed in said patent by American Cyanamid Company, and was the preferred compound taught by said patent and the one commercialized from among the derivatives described and claimed therein.
Subsequently, U.S. Reissue Pat. No. 26,833 and U.S. Pat. Nos. 4,824,847; 4,855,299; 4,861,758 and 5,215,993 all relate to the coccidiocidal properties of halofuginone, while U.S. Pat. No. 4,340,596 teaches that it can also be used for combatting theileriosis.
In U.S. Pat. No. 5,449,678, there is described and claimed an anti-fibrotic composition, comprising an amount of a compound of formula I: ##STR2## wherein: n 1 or 2 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy;
R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl;
effective to inhibit collagen type I synthesis, as active ingredient therein, and the physiologically acceptable salts thereof.
After further research and development, it has now been discovered that the above-identified compounds of formula I are effective in the inhibition of restenosis, which formally is not a fibrotic condition.
The pathogenesis of atherosclerosis involves abnormal migration and proliferation of smooth muscle cells (SMCs) infiltrated with macrophages and embedded in extracellular matrix (ECM) of adhesive glycoproteins, proteoglycans and collagens V. Fuster, et al., "The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes," New Eng. J. Med., Vol. 326, pp. 242-250 (1992); R. Ross, "The Pathogenesis of Atherosclerosis: A Perspective for the 1990's," Nature, Vol. 362, pp. 801-809 (1993)!. Under physiological conditions, the majority of arterial SMCs remains in the Go phase and cell growth is controlled by a balance between endogenous proliferation-stimulating and proliferation-inhibiting factors. Following endothelial cell perturbation due to atherogenic risk factors (i.e., hypertension, hyperlipoproteinemia, diabetes mellitus), platelets and non-platelet-derived growth factors and cytokines are released and stimulate monocyte and SMC migration as well as SMC proliferation (V. Fuster, et al., ibid.; R. Ross, ibid.). Among these growth factors are platelet-derived growth factor (PDGF) G. A. A. Ferns, et al., "Inhibition of Neoinitmal Smooth Muscle Accumulation after Angioplasty by an Antibody to PDGF," Science, Vol. 253, pp. 1129-1132 (1991)!, basic fibroblast growth factor (bFGF) V. Lindner, et al., "Role of Basic Fibroblast Growth Factor in Vascular Lesion Formation," Circ. Res., Vol. 68, pp. 106-113 (1991)!, and interleukin-1 (IL-1) H. Loppnow and P. Libby, "Proliferating or Interleukin-1 Activated Human Vascular Smooth Muscle Cells Secrete Copious Interleukin 6, " J. Clin. Invest., Vol. 85, pp. 731-738 (1990)!. Macrophages and platelets also release enzymes, i.e., elastase, collagenase, heparanase) that digest various constituents of the ECM and release bFGF and possibly other growth factors (TGFB) that are stored in basement membranes and ECM I. Vlodavsky, et al., "Extracellylar Matrix-bound Growth Factors, Enzymes and Plasma Proteins," in: Molecular and Cellular Aspects of Basement Membranes, Monographs in Cell Biology, D. H. Rohrbach and R. Timpl, Eds., Academic Press, New York, N.Y., U.S.A., pp. 327-346 (1993)!. A potent growth-promoting activity towards SMCs is also exerted by thrombin, which, under certain conditions, may be present within the vessel wall R. Bar-Shavit, et al., "Thrombin Immobilized to Extracellular Matrix Is a Mitogen for Vascular Smooth Muscle Cells: Non-Enzymatic Mode of Action," Cell Reg., Vol. 1, pp. 453-463 (1990); S. M. Schwartz, "Serum-Derived Growth Factor is Thrombin?" J. Clin. Invest., Vol 91, p. 4 (1993)!. Molecules that interfere with the growth-promoting activity of these growth factors may attenuate the progression of the atherogenic process.
Proliferation of arterial smooth muscle cells (SMC) in response to endothelial injury is a basic event in the process of restenosis of coronary arteries after percutaneous transluminal coronary angioplasty (PTCA) V. Fuster, et al., ibid.!. Coronary bypass surgery or angioplasty are applied to reopen coronary arteries that have been narrowed by heart disease. A major problem with both procedures is that arteries rapidly reclog in about 30% of patients undergoing angioplasty and about 10% of bypass surgery patients. Vascular SMC are ordinarily protected by the smooth inner lining of the arteries, composed of vascular endothelial cells. However, following bypass surgery or angioplasty, SMC are often left exposed. In a futile effort to repair the wound, the cells proliferate and clog the artery.